Daclatasvir in Combination With Sofosbuvir With Or Without Ribavirin Is Safe and Efficacious in Liver Transplant Recipients With HCV Recurrence:

Interim Results of a European Multicenter Compassionate Use Program

Herzer K,1 Welzel TM,2 Ferenci P,3 Petersen J,4 Gschwantler M,5 Cornberg M,6 Berg T,7 Spengler U,8 Weiland O,9 Van der Valk M,10 Klinker H,11 Rockstroh J,8

Schott E,12 Peck-Radosavljevic M,3 Zhou Y,13 Jimenez-Exposito MJ,13 Zeuzem S2

1Universitätsklinikum Essen (AöR), Essen, Germany; 2Universitätsklinikum der Johann Wolfgang Goethe Universität, Frankfurt, Germany; 3Medizinische Universität Wien, Vienna, Austria; 4IFI Institut für Interdisziplinäre

Medizin, Hamburg, Germany; 5Wilhelminenspital, Vienna, Austria; 6Medizinische Hochschule Hannover, Hannover, Germany; 7Universitätsklinikum Leipzig, Leipzig, Germany; 8Universitätsklinikum Bonn, Bonn, Germany; 9Karolinska

University Hospital, Karolinska Institutet, Stockholm, Sweden; 10Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; 11Universitätsklinikum Würzburg, Würzburg, Germany; 12Charité

Universitätmedizin Berlin; Berlin, Germany; 13Bristol-Myers Squibb, Princeton, NJ, USA.

The Liver Meeting 2015®San Francisco, CA, 13–17 November 2015

■ Recurrence of HCV infection after liver transplantation is common and a significant threat to graft and patient survival1

■ Interferon-free oral therapies are well tolerated and can achieve high SVR rates with shorter treatment durations and minimal drug-drug interactions

■ The pan-genotypic combination of DCV + SOF + RBV has shown high SVR12 rates (GT 1, 95%; GT 3, 91%) and good tolerability in patients with post-liver transplant HCV recurrence after 12 weeks of therapy (ALLY-1 study)2

■ A European compassionate use program (CUP) provided access to DCV before market authorization to patients in urgent need of treatment

■ Here we report findings on DCV + SOF RBV in liver transplant recipients with HCV recurrence enrolled in the European CUP (AI444-237)3

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Background

RBV, ribavirin; DCV, daclatasvir (NS5A inhibitor); SOF, sofosbuvir (NS5B inhibitor)1. Narang, et al. Liver Transpl 2010; 16:1228–1235; 2. Poordad, et al. EASL, 50th ICL 2015. Abstract L08; 3. Clinical trials.gov, https://clinicaltrials.gov/ct2/show/NCT02097966.

European DCV Compassionate Use Program

Inclusion criteria■ Age ≥ 18 years with no treatment options ■ High risk of hepatic decompensation or

death within 12 months if left untreated– Or urgent need of viral clearance

(extrahepatic manifestations/comorbidities)

Exclusion criteria■ Creatinine clearance ≤ 30 mL/min■ Pregnancy or not using contraception

Primary objective: To provide access to DCV to patients with life-threatening chronic HCV infection who have no other treatment options

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Week 24# Week 36Day 1

DCV (60 mg)* + SOF (400 mg) ± RBV† Follow-Up

SVR12‡

Primary endpoint

Additional Optional Follow-Up

Week 48 Week 72

SVR24

#Addition of RBV and shorter duration of treatment at the discretion of the physician

*Dose adjusted for concomitant ARVs‡HCV RNA < LLOQ, TD or TND at post treatment Week 12 (next value carried backward approach)

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All Treated Liver Transplant Patients with HCV recurrence

N = 87

Efficacy PopulationN = 80

Excluded from this interim analysis, N = 7a

■ Did not reach post-treatment Week 12, n = 3; ■ Informed consent withdrawal, n = 1■ Missing data (not caused by death or

treatment discontinuation due to AE), n = 3

Safety PopulationN = 87

Populations and Statistical Analysis

■ Primary Efficacy Analysis (mITT): – HCV RNA < LLOQ, TD or TND at post-treatment Week 12 (next value carried backward)

– Patients with missing data who died, discontinued treatment due to AEs, or had virologic breakthrough / relapse before post-treatment Week 12 were classified as failures

■ Safety Analysis: – Clinical (AE, serious AE, AE leading to discontinuation and death) and laboratory

abnormalitiesaAll excluded patients had HCV RNA < LLOQ TD or TND at EOT (Week 24) or at the last available assessment (On-treatment Week 12).

All Treated PatientsN = 485

ParameterDCV + SOF

N = 62DCV + SOF + RBV

N = 25All Patients

N = 87Age, median (range) yr 58 (40–75) 58 (39–74) 58 (39–75)Male, n (%) 46 (74) 15 (60) 61 (70)White, n (%)a 59 (95) 22 (88) 81 (93)HCV genotype, n (%) 1a 21 (34) 7 (28) 28 (32) 1b 32 (52) 9 (36) 41 (47) 1 subtype unknown 5 (8) 2 (8) 7 (8) 3 4 (6) 4 (16) 8 (9) 4 0 2 (8) 2 (2) Unknown 0 1 (4) 1 (1)HCV RNA, median (range) log10 IU/mLa 6.3 (0–7.5) 6.2 (0–7.2) 6.2 (0–7.5) HCV RNA ≥ 2,000,000 IU/mL, n (%)a 30 (48) 10 (40) 40 (46)ALT, median (range) IU/La 55 (9–347) 49 (14–235) 53 (9–347)Albumin, median (range) g/La 41 (20–49) 41 (24–47) 41 (20–49)Prior HCV therapy, n (%) 41 (66) 19 (76) 60 (69)HBV coinfection, n (%) 3 (5) 2 (8) 5 (6)a Excludes patients with missing data.

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Demographic and Baseline Disease Characteristics

6

Baseline Disease Characteristics

ParameterDCV + SOF

N = 62DCV + SOF + RBV

N = 25All Patients

N = 87Time since LT, median (range) years 3.9 (0.3–21.5) 2.2 (0.3–9.1) 3.4 (0.3–21.5)Cirrhosis, n (%)a 24 (39) 13 (52) 37 (43)

Child-Pugh class, n (%)b

A 12 (50) 9 (69) 21 (57) B 8 (33) 4 (31) 12 (32)

C 4 (17) 0 4 (11)MELD score, median (range) 10 (6–25) 10 (6–18) 10 (6–25)MELD score > 15, n (%)b 7 (29) 1 (8) 8 (22)

Fibrosing cholestatic hepatitis, n (%) 8 (13) 2 (8) 10 (11)Immunosuppressive therapy, n (%)c

Tacrolimus 44 (71) 20 (80) 64 (74) Cyclosporine 15 (24) 3 (12) 18 (21) Everolimus 6 (10) 4 (16) 10 (11)

Sirolimus 2 (3) 0 2 (2) Mycophenolate 30 (48) 14 (56) 44 (51)

Prednisone/prednisolone 11 (18) 3 (12) 14 (16)

a Diagnosed by liver biopsy (Metavir >F3, Ishak >4, or the equivalent), n=2; FibroScan (>14.6 kPa), n=19; or FIB-4 score (>3.25), n=16; b Percentages based on cirrhotic patients; c Excludes patients with missing data.

Primary Efficacy Analysis – SVR12 (mITT)

7

0

20

40

60

80

100 91 93

DCV + SOFDCV + SOF + RBVOverall

5458

2022

7480H

CV R

NA

< LL

OQ

, TD

or T

ND

%

± 9

5% C

I

■ 75 of 80 patients treated for 24 weeks; 72 of these 75 (96%) achieved SVR12

Not Achieving SVR12 4 2 6

Breakthrough or relapse 0 0 0

Discontinuation (AE) 0 1 1

Deathsa 4 1 5

a 3 deaths occurred during post-treatment follow-up.

Primary Efficacy Analysis – SVR12 (mITT)

7

0

20

40

60

80

100 91 93

DCV + SOFDCV + SOF + RBVOverall

5458

2022

7480H

CV R

NA

< LL

OQ

, TD

or T

ND

%

± 9

5% C

I

■ 75 of 80 patients treated for 24 weeks; 72 of these 75 (96%) achieved SVR12

Not Achieving SVR12 4 2 6

Breakthrough or relapse 0 0 0

Discontinuation (AE) 0 1 1

Deathsa 4 1 5

a 3 deaths occurred during post-treatment follow-up.

SVR12 (mITT) by HCV Genotype

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All GT 1ᵃ 1a 1b 3 40

20

40

60

80

100 93 95 94100

94100 100 100 100

1920

77

3032

88

33

44

00

11

HCV genotype b

DCV + SOF DCV + SOF + RBV

HCV

RN

A <

LLO

Q, T

D o

r TN

D, %

5155

1516

aGT 1 subtype unknown in 4 patients: DCV + SOF (n = 3); DCV + SOF + RBV (n = 1); 2 patients achieved SVR12; 1 patient in each arm died.b Excludes 1 patient (DCV + SOF + RBV) with unknown GT; patient discontinued Day 58 due to AE (treatment failure).

Cirrhosisᵃ A B or C ᵇ < 10 ≥ 10 ᶜ FCH0

20

40

60

80

100 9788

100

75

9283

75

100

8288

67

100

60

100

SVR12 (mITT) by Liver Disease Status

9

2124

1212

911

DCV + SOF DCV + SOF + RBV

78

2829

912

1010

23

1112

66

1012

35

Child-Pugh class MELD score

HCV

RN

A <

LLO

Q, T

D o

r TN

D, %

FCH, fibrosing cholestatic hepatitis.a Excludes 6 patients with indeterminate cirrhosis status (5 DCV + SOF; 1 DCV + SOF + RBV); all achieved SVR12.

b 4 patients (DCV + SOF) had Child-Pugh class C; 3 of 4 achieved SVR12.c 5 patients had MELD scores 16–20 (2 of 5 achieved SVR12); 3 patients had MELD scores 21–25 (all SVR12).

68

22

NoCirrhosisa

< 2 × 10⁶ ≥ 2 × 10⁶ 30 – 59 60 – 89 ≥ 900

20

40

60

80

10086

10092

100 100

83

100

86

100 100

SVR12 (mITT) by Baseline Characteristics

9

2529

2828

1012

DCV + SOF DCV + SOF + RBV

99

2426

67

1010

22

1212

22

HCV RNA, IU/mL a Creatinine clearance, mL/min b

HCV

RN

A <

LLO

Q, T

D o

r TN

D, %

a Excludes 2 patients with missing HCV RNA data at baseline.b 3 patients (DCV + SOF) had CrCl < 30 at baseline; 2 of 3 achieved SVR12.

Changes in Liver Disease Parameters From Baseline to Post-Treatment Week 12

11Data indicate median, IQR, range.

ALT

Baseline Follow-up0

255075

100125

300400

IU/m

L

Albumin

Baseline Follow-up0

102030405060

mg/

L

Platelets

Baseline Follow-up0

100

200

300

400

500

plat

elet

s/L

(×10

9 )

Albumin Platelets

ALT

N = 73N = 86

N = 71N = 87N = 57N = 75

g/L

IU/L

plat

elet

s ×

109 /

L

Total Bilirubin

Baseline Follow-up0

25

50

200

300

IU/m

L

Total Bilirubin

N = 69N = 77

mg/

dLm

g/dL

μmol

/L

On-Treatment Safety Summary

Patients, n (%)DCV + SOF

N = 62DCV + SOF + RBV

N = 25All Patients

N = 87Total AEs 34 (55) 17 (68) 51 (59)Serious AEs 10 (16) 6 (24) 16 (18)Treatment-related serious AE 1 (2) 2 (8) 3 (3)

Renal impairment 1 1 2Pancytopenia - 1 1

AEs leading to discontinuation or deatha 4 (7) 4 (16) 8 (9)Deathsb 1 (2) 1 (4) 2 (2)

Sepsis 1 1Spontaneous bacterial peritonitis - 1 1

Graft rejection events 0 0 0Treatment-emergent grade 3 or 4 laboratory abnormalities

Hemoglobin < 90 g/L 5 (8) 5 (20) 10 (11)ALT > 5 × ULN 1 (2) 0 1 (1)AST > 5 × ULN 1 (2) 0 1 (1)Total bilirubin > 2.5 × ULN 1 (2) 1 (5) 2 (3)Creatinine > 1.9 × ULN 5 (8) 0 5 (6)

a Treatment-related events included renal impairment (n=2), seborrheic dermatitis (n=1), and dyspnea (n=1).b All deaths were considered unrelated to program therapy.

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■ No significant changes in immunosuppressive regimens were required

Summary and Conclusion

■ In a real-world setting, DCV + SOF ± RBV achieved a high SVR12 rate (93%) in 80 liver transplant recipients with recurrent HCV infection– High SVR12 rate regardless of HCV genotype, cirrhosis status or RBV use

– No virologic breakthrough or relapse

■ Median ALT, bilirubin, and albumin levels improved between baseline and post-treatment Week 12

■ DCV + SOF ± RBV was generally safe and well tolerated– Few discontinuations due to adverse events, treatment-related serious AE, or

grade 3 or 4 laboratory abnormalities

■ These results suggest that the pangenotypic, all-oral combination of DCV + SOF + RBV represents an effective and well-tolerated treatment for liver transplant recipients with recurrent HCV, including patients with advanced disease

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Acknowledgments

■ The authors thank the patients and their families, and physicians and research staff at all program sites

■ Editorial support was provided by R Boehme of Articulate Science and was funded by Bristol-Myers Squibb

■ ClinicalTrials.gov registration number NCT02097966

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